Airway smooth muscle (ASM) has a multifaceted and deleterious role in asthma. ASM contraction and impaired relaxation cause acute and persistent airflow obstruction, and it contributes to airway inflammation by secreting cytokines, modifying tissue matrix, and binding migrating inflammatory cells. Its excessive accumulation in asthma amplifies these actions. These adverse roles make intervention to reduce ASM mass an attractive strategy for novel asthma therapies. Our preliminary studies in model systems (cultured airway myocytes and transgenic TGF[unreadable]-overexpressing mice that develop ASM overaccumulation and constrictor hyperresponsiveness) suggest that treatment with statins can accomplish this goal. We propose a clinical trial to determine whether treatment with statins reduces the mass of ASM in severe persistent asthma, a condition that remains ineffectively treated with current therapies in many patients. We will plan a 52 week double-masked, placebo-controlled phase II clinical trial of lovastatin in volunteers with severe persistent asthma. Subjects will undergo bronchoscopy before and at the conclusion of lovastatin or placebo treatment, and endobronchial biopsies will be collected to evaluate ASM mass, the reduction of which by lovastatin is the primary outcome measure. [unreadable] [unreadable] Secondary outcomes will evaluate the influence of lovastatin treatment on other aspects of ASM structure and function; on airway inflammation and lung function; and on asthma-related health outcomes (including symptom control, exacerbations, and asthma-related health care utilization). During the proposed one-year planning period, we will finalize the study design, regulatory considerations, operational procedures, and ethical analysis of this clinical trial; by the end of this period, we will be prepared to begin enrollment in the proposed trial. The information to be gathered in the proposed clinical trial should reveal whether lovastatin treatment alters ASM structure and function in asthma, which major inflammatory pathways are targeted in its effect, and whether the ASM changes are associated with improvements in airway function or asthma-related health outcomes, and will provide information required for the planning of any future clinical trials. Demonstration of positive biological or clinical effects of statins in severe asthma would justify their further development as novel asthma medicines. [unreadable] [unreadable] [unreadable]